This invention relates to a process for the production of 3-hemisulfate sodium salts of 17.alpha.-hydroxy steroids of the general Formula I ##STR2## wherein R.sub.1 is hydrogen, methyl or ethyl and .DELTA. represents one or more additional double bonds optionally present in either or both of rings B and C.
These compounds are valuable pharmaceuticals and can be utilized, due to their estrogenic activity, inter alia, for mitigating the physical and mental complaints connected with the climacteric.
A combination of compounds of Formula I wherein R.sub.1 is methyl and wherein, firstly, there is no additional double bond (sodium 17.alpha.-estradiol-3-hemisulfate), secondly, a .DELTA..sup.7 -double bond is present (sodium 17.alpha.-dihydroequilin-3-hemisulfate), and, thirdly, the .DELTA..sup.6,8 -double bonds are present (sodium 17.alpha.-dihydroequilenin-3-hemisulfate), are components of medicinal preparations obtained as a mixture ("natural conjugated estrogens") together with the corresponding 17-ketones from the urine of pregnant mares.
The ratio of the individual estrogens in the pregnant mare urine, however, is dependent on the stage of the pregnancy. The resulting fluctuations must be compensated for by the addition of varying amounts of the individual components (Canadian Pat. Nos. 691,988 and 922,627) in order to produce a uniform product.
A synthetic process is known for the manufacture of sodium estradiol-3-hemisulfate. This process is disclosed in Canadian Pat. Nos. 482,630 and 482,631. (For the novel nomenclature employed, see, for example, "Steroids," Fieser and Fieser, publishers Chemie/Weinheim, pp. 511-512.)
This synthesis involves three separate stages. In the first stage, 17.alpha.-estradiol-17-acetate is reacted with chlorosulfonic acid in pyridine to produce 17.alpha.-estradiol-3-hemisulfate-17-acetate pyridinium salt. In the second stage, this pyridinium salt is converted, with sodium hydroxide, to the sodium 17.alpha.-estradiol-17-acetate-3-hemisulfate. In the third stage, the latter compound is saponified in the presence of aqueous alkali hydroxide by heating to 100.degree. C. to the sodium salt of 17.alpha.-estradiol-3-hemisulfate. This process is relatively complicated, due to the isolation twice of intermediate products by precipitation with ether and the very expensive extraction of the final product in acetone. Also, the thus-attained overall yields are only around 35% of theory.
It is an object of the present invention to provide a simple synthetic method for the production of sodium hemisulfates of aromatic A-ring 3,17.alpha.-dihydroxy estrogens. Other objects will be apparent to those skilled in the art.